The long-term objective of this proposal for renewal of a Research Scientist Award is to identify the biological mechanisms that control meal size in animals and humans. Identification of these mechanisms will permit manipulation of them for therapy of the hyperphagia that occurs in at least some forms of human obesity and is a hallmark of bulimia nervosa. The current proposal is designed to analyze the effect of food stimuli acting primarily preabsorptively on meal size in normal rats, in rats with ventromedial hypothalamic obesity (VMH), and in Zucker (fa/fa) rats with genetic obesity. The major aim of the proposal is to measure as independently as possible the stimulating and satiating effects of sucrose and fat on meal size. This will be done by exploiting the differential localization of these effects along the gut -- the mouth is the predominant site for the stimulating effect, and the stomach, small intestine, and liver are the predominant sites for the satiating effect. Four specific hypotheses are tested -- dopaminergic mediation of the positive reinforcing effect of sucrose and fat, vagal afferent mediation of the satiating effect of sucrose and fat in the stomach and in the small intestine, and the satiating effect of endogenous cholecystokinin in the small intestine and in the brain, and the modulating effects of serotonergic and female sex hormones on the satiating effect of peripheral cholecystokinin. Methods include sham feeding, chronic duodenal catheterization, pyloric cuff, HPLC-electrochemical detection, radiofrequency lesion, selective afferent and efferent vagotomy, quantitative receptor autoradiography, and specific -antagonists of cholecystokinin. A pervasive theme of these experiments is to search for differences between male and female rats in the potency or kind of mechanisms that control meal size in lean or neurologically or genetically (fa/fa) obese rodents.